It has been known since the 1960s that MGBG exhibits anti-tumor activity in various cancer cells. In fact MGBG was shown to be very effective as an antineoplastic agent, and even produced complete remission in trials involving patients with leukemia. Other cancers that were treated by the administration of MGBG in early studies include breast, esophagus, colon, rectal, and kidney. Unfortunately, the use of MGBG in an anti-cancer regimen proved to be unacceptably toxic, resulting in its gradual withdrawal from clinical trials. See Int. J. Cancer, vol. 26, 571 (1980). In the 1970s and 1980s MGBG underwent a bit of a revival, being tested as an anti-cancer agent in subjects with lymphomas, including Hodgkin's, Non-Hodgkin's and AIDS-related lymphoma. See Annals of Oncology, vol. 5, p. 487 (1994); J. Clinical Onc., vol. 15, no. 3, p. 1094 (1997); Invest. New Drugs, vol. 1, p. 235 (1983); and Blood, vol. 57, no. 6 (1981). Again, however, as used in the anti-cancer regimens involved in these studies, MGBG exhibited significant toxicity. The common focus of all of these studies and trials was the ability of MGBG to act as an anti-tumor agent, a characteristic attributed to its role in the inhibition of the enzyme S-adenosyl-L-methionine decarboxylase which catalyzes the synthesis of spermidine. See, for example, Cancer Treatment Reports, vol. 63, no. 11-12, p. 1933 (1979). None of these studies recognized the potential of MGBG as an antiviral agent.
Human immunodeficiency virus (HIV) causes an infection for which researchers have long sought effective antiviral agents. Patients infected with HIV experience a variable but progressive decline in immune function resulting in clinically apparent opportunistic infections and other diseases. Studies have shown that the long term prognosis in HIV infected patients is dictated by the blood cell level of HIV DNA present at the initiation of infection. As the DNA form is a relatively long lived, mostly host cell DNA integrated form of the virus, this high HIV DNA load suggests that patients who have a larger HIV DNA reservoir do worse clinically that do those with lower levels of HIV DNA.
HIV is an RNA retrovirus, that upon successful infection of a host cell, reverse transcribes its genomic RNA into DNA, which then, in a double stranded form, integrates into susceptible host cells. The major targets for infection in vivo are the CD4 expressing T cells and macrophages. Whereas T cells, upon activation of the HIV DNA into an infectious RNA form, generally get killed, the virus expressing macrophages don't die after infection and likely serve as the long term HIV DNA reservoir in vivo.
At least one study on the HIV reservoir has provided half life estimates of 4 years for infected blood macrophages and less than 2 years for infected T cells. Both values help explain the reason for the failure of highly active antiretroviral therapy (HAART) to clear the virus in vivo. More recently, studies on the HIV DNA sequence in vivo showed that in HIV plasma viral load negative subjects on HAART HIV replication continued to occur in vivo within macrophages but not T cells. Therefore, the longest lived reservoir of HIV in vivo is the macrophage.
Other recent studies have confirmed the long lived nature of HIV infected macrophages in vivo. For example, it has been shown that the ancestral form of HIV in vivo in a patient who died of AIDS related dementia resided within macrophages in the outer membrane covering of the brain (meningeal layer). Viral sequences present in this long lived reservoir gave rise to all of the sequences residing in other portions of the brain as well as the peripherally located seminal vesicles and lymph nodes. Another study has suggested a mechanism for the long lived nature of HIV infected macrophages. This study mapped HIV DNA insertion sites within macrophages in tissues from patients with late stage AIDS. All of the insertion sites were within genes near activation genetic loci that, if activated through an HIV insertional process, would keep the infected macrophages in a persistently activated and essentially immortal state.
Considering that HAART only keeps new cells from becoming infected with HIV, any cell already containing HIV DNA would be resistant to drug effects. It's therefore no surprise that upon discontinuation of HAART most HIV infected patients rapidly develop high HIV plasma viral loads because the reservoir initiates new rounds of primary infection, presumably in part because of the infected macrophage reservoir. Therefore, in order to impact the HIV reservoir, a drug must be able to kill the infected macrophages and have a less toxic effect on normal macrophages.
Many recent studies have focused on trying to identify the phenotype of infected macrophages in blood. For example, it has been shown that in AIDS dementia patients where the infected macrophage is known to circulate in the blood as well as cause disease in vivo, that the pathogenic cell expressed CD14 as well as CD16 and elevated levels of the activation marker, HLA-DR. It has also been shown that this same type of macrophage also expressed the proliferation marker, proliferating cell nuclear antigen (PCNA) and upon transfer into a mouse this macrophage caused an end stage AIDS-like lymphoma. Therefore, pathogenic macrophages associated with HIV infection in general express CD14, elevation of HLA-DR, higher levels of CD16 and PCNA. Within this population of cells resides the blood form of the long lived HIV DNA reservoir. Therefore, if a drug could kill only the pathogenic macrophage population leaving the normal macrophages less effected, it would be expected to also kill the macrophage associated HIV DNA reservoir.